Epigenetic regulation in adult neural stem cells.

Neural stem cells (NSCs) exhibit self-renewing and multipotential properties. Adult NSCs are located in two neurogenic regions of adult brain: the ventricular-subventricular zone (V-SVZ) of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Maintenance and differentiation of adult NSCs are regulated by both intrinsic and extrinsic signals that may be integrated through expression of some key factors in the adult NSCs. A number of transcription factors have been shown to play essential roles in transcriptional regulation of NSC cell fate transitions in the adult brain. Epigenetic regulators have also emerged as key players in regulation of NSCs, neural progenitor cells and their differentiated progeny via epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling and RNA-mediated transcriptional regulation. This minireview is primarily focused on epigenetic regulations of adult NSCs during adult neurogenesis, in conjunction with transcriptional regulation in these processes.

Development and validation of a risk model with variables related to non-small cell lung cancer in patients with pulmonary nodules: a retrospective study.

BACKGROUND: Lung cancer is a major global threat to public health for which a novel predictive nomogram is urgently needed. Non-small cell lung cancer (NSCLC) which accounts for the main port of lung cancer cases is attracting more and more people's attention. PATIENTS AND METHODS: Here, we designed a novel predictive nomogram using a design dataset consisting of 515 pulmonary nodules, with external validation being performed using a separate dataset consisting of 140 nodules and a separate dataset consisting of 237 nodules. The selection of significant variables for inclusion in this model was achieved using a least absolute shrinkage and selection operator (LASSO) logistic regression model, after which a corresponding nomogram was developed. C-index values, calibration plots, and decision curve analyses were used to gauge the discrimination, calibration, and clinical utility, respectively, of this predictive model. Validation was then performed with the internal bootstrapping validation and external cohorts. RESULTS: A predictive nomogram was successfully constructed incorporating hypertension status, plasma fibrinogen levels, blood urea nitrogen (BUN), density, ground-glass opacity (GGO), and pulmonary nodule size as significant variables associated with nodule status. This model exhibited good discriminative ability, with a C-index value of 0.765 (95% CI: 0.722-0.808), and was well-calibrated. In validation analyses, this model yielded C-index values of 0.892 (95% CI: 0.844-0.940) for external cohort and 0.853 (95% CI: 0.807-0.899) for external cohort 2. In the internal bootstrapping validation, C-index value could still reach 0.753. Decision curve analyses supported the clinical value of this predictive nomogram when used at a NSCLC possibility threshold of 18%. CONCLUSION: The nomogram constructed in this study, which incorporates hypertension status, plasma fibrinogen levels, BUN, density, GGO status, and pulmonary nodule size, was able to reliably predict NSCLC risk in this Chinese cohort of patients presenting with pulmonary nodules.

Recent Advances of Using Exosomes as Diagnostic Markers and Targeting Carriers for Cardiovascular Disease.

Cardiovascular diseases (CVDs) are the leading cause of human death worldwide. Exosomes act as endogenous biological vectors; they possess advantages of low immunogenicity and low safety risks, also providing tissue selectivity, including the inherent targeting the to heart. Therefore, exosomes not only have been applied as biomarkers for diagnosis and therapeutic outcome confirmation but also showed potential as drug carriers for cardiovascular targeting delivery. This review aims to summarize the progress and challenges of exosomes as novel biomarkers, especially many novel exosomal noncoding RNAs (ncRNAs), and also provides an overview of the improved targeting functions of exosomes by unique engineered approaches, the latest developed administration methods, and the therapeutic effects of exosomes used as the biocarriers of medications for cardiovascular disease treatment. Also, the possible therapeutic mechanisms and the potentials for transferring exosomes to the clinic for CVD treatment are discussed. The advances, in vivo and in vitro applications, modifications, mechanisms, and challenges summarized in this review will provide a general understanding of this promising strategy for CVD treatment.

Conservative Versus Endovascular Treatment for Spontaneous Isolated Superior Mesenteric Artery Dissection: A Clinical and Imaging Follow-up Study.

PURPOSE: Spontaneous isolated superior mesenteric artery dissection (SISMAD) is a rare vascular disease, the treatment strategies for which remain debated. This retrospective study aimed to compare the outcomes of conservative and endovascular treatments in patients with SISMAD. MATERIALS AND METHODS: Fifty-eight patients with SISMAD confirmed by computed tomography angiography admitted to our hospital between November 2017 and May 2021 and received confirmed conservative (n=43) or endovascular (n=15) treatment. The patient demographics, imaging analysis, and follow-up results were analyzed and compared. RESULTS: The cohort included 54 males and 4 females with a mean age of 52 years. Abdominal pain was the major complaint (49/58, 84.5%), followed by chest pain (2/58, 3.4%). The mean follow-up was 9.1±7.9 months. The 2 main Sakamoto types were type III (27/58, 46.6%) and type IV (16/58, 27.6%). Most patients in both groups had angle 1 (aortomesenteric angle) and angle 2 (superior mesenteric artery [SMA] course) of over 80°. About 67.3% of patients had long length of dissection (>60 mm). The median distance between the SMA root and the dissection entry site was 1.5 cm, mostly (84.5% of the patients) in the curved segment of the SMA. Telephone follow-ups found that most patients survived pain-free, and none underwent intestinal resection. Only 4 patients, 2 in each group, had recurrent abdominal pain during follow-up and received stenting treatment to achieve complete vascular remodeling. Importantly, we found that the conservative and endovascular therapies achieved similar high remodeling rates (94% and 100%, respectively; p=0.335). The conservative group achieved satisfying vascular remodeling (partial, 35%; complete, 59%), making it as safe and effective a treatment as endovascular therapy. CONCLUSIONS: Initial conservative management is safe and effective in patients with SISMAD. A high technical success rate and favorable short-term outcomes were associated with endovascular procedures as secondary interventions. It would be helpful to conduct large-scale, prospective, randomized controlled trials with long-term follow-up for SISMAD. CLINICAL IMPACT: 1. This research provided more detail clinical information, such as evaluation of abdominal pain and measurements of SMA angles, which is all relevant to treatment. 2. What's more, the most surprising results of follow-up part shown that conservative treatment could reached the remodeling rate as high as endovascular treatment, which was relatively low in other studies. It helps us share our treatment experience with clinicians. 3. In addition, we get limited knowledge about this rare disease, it's encouraging us to do more researches based on the results we had.

Curcumin Analog, HO-3867, Induces Both Apoptosis and Ferroptosis via Multiple Mechanisms in NSCLC Cells with Wild-Type p53.

Over the last decade, researchers have paid more and more attention to the natural compound curcumin for its potential application in anticancer therapy. However, the application of curcumin has been limited owing to its rapid metabolism in the body. HO-3867, a stable curcumin analog, shows potent antitumor activities against various tumor cells. Yet, information on HO-3867's impact on non-small-cell lung cancer (NSCLC) cells is lacking. Herein, we evaluated the cytotoxicity of HO-3867 in NSCLC cells. We discovered that HO-3867 suppressed the viability of NSCLC cells containing wild-type p53. In NSCLC cells, HO-3867 promotes both apoptosis and ferroptosis, the latter of which is a newly discovered mode of cell death. Mechanically, HO-3867-induced apoptosis relied on the inhibition of Mcl-1 and Bcl-2 and the upregulation of Bax. Moreover, NSCLC cells undergo ferroptosis when treated with HO-3867 via activating the p53-DMT1 axis and suppressing GPX4. Additionally, HO-3867 caused an accumulation of reactive oxygen species (ROS) in NSCLC in a way that was dependent on the presence of iron. Our findings point to the possibility that HO-3867 might be employed as a therapeutic agent for treating NSCLC.

Mechanisms and application strategies of miRNA­146a regulating inflammation and fibrosis at molecular and cellular levels (Review).

In the progression of various diseases, inflammation has a critical role. Chronic persistent inflammation is a pivotal trigger of fibrosis. Several microRNAs (miRNAs) participate in inflammation and fibrosis. In recent years, it has been proved that miRNAs are a critical link in physiological and pathological processes. Among them, the miRNA miR­146a has a pivotal role in the immune system and acquired immunity, making it one of the most studied miRNAs. Due to its essential roles at the molecular and cellular levels, it has broad application prospects in precision medicine. The present comprehensive review focused on the mechanisms of miR­146a and its application strategies in inflammation and fibrosis, discussing its therapeutic potential. The main signaling pathways through which miR­146a regulates inflammation and fibrosis and their relationships were covered. Furthermore, the functions and effects of miR­146a in specific cells, which may join in the process of inflammation and fibrosis, were outlined. Application strategies were also summarized according to recent studies based on these mechanisms.

A lung cancer risk prediction model for nonsmokers: A retrospective analysis of lung nodule cohorts in China.

BACKGROUND: The risk of lung cancer in nonsmokers is increasing; however, there are relatively few studies on the risks of lung cancer in nonsmokers. PATIENTS AND METHODS: We collected epidemiological and clinical data from 429 nonsmoking patients with lung nodules from the Affiliated Li Huili Hospital as a training cohort and 123 nonsmoking patients with lung nodules as a testing cohort. We identified variables that might be related to malignant lung nodules from 27 variables by performing least absolute shrinkage and selection operator analysis. Univariate and multivariate analyses of these variables were conducted using binary logistic regression. Significant variables were used to generate a lung cancer risk prediction model for nodules in nonsmokers. RESULTS: We successfully constructed a predictive nomogram incorporating density, ground-glass opacities, pulmonary nodule size, hypertension, plasma fibrinogen levels, and blood urea nitrogen. This model exhibited good discriminative ability, with a C-index value of 0.788 (95% confidence interval [CI]: 0.742-0.833) in the training cohort and 0.888 (95% CI: 0.835-0.941) in the testing cohort; it was well-calibrated in both cohorts. Decision curve analyses supported the clinical value of this predictive nomogram when used at a lung cancer possibility threshold of 18%. Ten-fold cross-validation indicated good stability and accuracy of the model (kappa = 0.416 ± 0.128; accuracy = 0.751 ± 0.056; area under the curve = 0.768 ± 0.049). CONCLUSION: Our risk model can reasonably predict the risks of lung cancer in nonsmoking Chinese patients with lung nodules.

Long Noncoding RNA HLA Complex Group 18 Improves the Cell Proliferation of Myocardial Fibroblasts by Regulating the Hsa-microRNA-133a/Epidermal Growth Factor Receptor Axis.

Hsa-microRNA (has-miR)-133a inactivates the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway and suppresses the cell proliferation of myocardial fibroblasts by downregulation of the epidermal growth factor receptor (EGFR) expression. Bioinformatics analysis exhibits extended noncoding RNA HLA complex group 18 (lncRNA-HCG18) binds to hsa-miR-133a. The purpose of the current experiment is to explore whether lncRNA-HCG18 adsorbed hsa-miR-133a through sponging, resulting in decreased inhibition of hsa-miR-133a on EGFR and ultimately promoting the proliferation of myocardial fibroblasts. To verify and study the correlation and mechanism between lncRNA-HCG18, hsa-miR-133a, and their target genes. Firstly, after overexpression/silencing of lncRNA-HCG18 in myocardial fibroblasts, the level of hsa-miR-133a expression was evaluated by quantitative reverse transcription-polymerase chain reaction (RT-qPCR), and the EGFR, ERK1/2, and p-ERK1/2 expression levels were assessed by Western blotting to confirm that upregulation of EGFR and p-ERK1/2 protein levels by overexpression of lncRNA-HCG18, siRNA lncRNA-HCG18 (siHCG18) reduced the EGFR and p-ERK1/2 protein levels. Then, the luciferase reporter gene system was used to verify that lncRNA-HCG18 regulated EGFR expression by inhibiting the function of the hsa-miR-133a regulatory target gene. Then, a RAP assay was used to confirm that lncRNA-HCG18 interacted with hsa-miR-133a. Finally, the analysis of CCK-8 results indicated that the cell proliferation of myocardial fibroblasts was significantly reduced by siHCG18 while reversed by overexpression of lncRNA-HCG18. Thus, lncRNA-HCG18 inhibited cell viability of cardiac fibroblasts via the hsa-miR-133a/EGFR axis, which was regarded as a regulator of cell proliferation of cardiac fibroblasts in cardiovascular diseases.

Multiple roles of apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) in human tumors: a pan-cancer analysis.

Although there have been some recent cell and animal experiments indicating that expression of the gene encoding apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) is closely related to cancer, it still lacks pan-cancer analysis. Here we analyzed the potential carcinogenic role of APOBEC3B in 33 tumors based on The Cancer Genome Atlas (TCGA). APOBEC3B was highly expressed in most tumors and weakly expressed in a few. Differences in expression level were significantly correlated with the pathological tumor stage and prognosis of affected patients. The high-frequency APOBEC3B changes were principally mutations and amplifications in some tumors, such as uterine corpus endometrial carcinomas or cutaneous melanomas. In testicular germ cell tumors and invasive breast carcinomas, APOBEC3B expression and CD8+ T lymphocyte counts were correlated. In other cancers, such as human papilloma virus (HPV)-related head and neck squamous cell carcinomas or esophageal adenocarcinomas, there was also cancer-associated fibroblast infiltration. The APOBEC3B enzyme acts in the mitochondrial respiratory electron transport chain and in oxidative phosphorylation. This first pan-cancer study provides a comprehensive understanding of the multiple roles of APOBEC3B in different tumor types.

Eukaryotic initiation factor 5A2 mediates hypoxia-induced autophagy and cisplatin resistance.

Hypoxia-induced cisplatin resistance is a major challenge during non-small cell lung cancer (NSCLC) treatment. Based on previous studies, we further explored the effect of eukaryotic initiation factor 5A2 (eIF5A2) in hypoxia-induced cisplatin resistance. In this study, we found that autophagy and cisplatin resistance were increased under hypoxic conditions in three different NSCLC cell lines. Compared with that under normoxic conditions, dramatic upregulation of eIF5A2 and hypoxia inducible factor 1 subunit alpha (HIF-1α) levels were detected under hypoxia exposure. Small interfering RNA silencing of HIF-1α resulted in decreased expression of eIF5A2, indicating that eIF5A2 acts downstream of HIF-1α. In addition, the expression of eIF5A2 was significantly higher in NSCLC tumors compared with that in normal tissues. RNA silencing-mediated downregulation of eIF5A2 decreased hypoxia-induced autophagy, thereby reducing hypoxia-induced cisplatin resistance in NSCLC cells. The roles of eIF5A2 in cisplatin resistance were further validated in vivo. Combined treatment using eIF5A2-targeted downregulation together with cisplatin significantly inhibited tumor growth compared with cisplatin alone in the subcutaneous mouse model. In conclusions, eIF5A2 overexpression is involved in hypoxia-induced autophagy during cisplatin resistance. We suggest that a combination of eIF5A2 targeted therapy and cisplatin chemotherapy is probably an effective strategy to reverse hypoxia-induced cisplatin resistance and inhibit NSCLC development.

A novel algorithm for lung adenocarcinoma based on N6 methyladenosine-related immune long noncoding RNAs as a reliable biomarker for predicting survival outcomes and selecting sensitive anti-tumor therapies.

BACKGROUND: Lung cancer is a highly heterogeneous malignant tumor with high incidence and mortality. Recently, increasing evidence has demonstrated that N6-methyladenosine (m6A) methylation and the tumor microenvironment (TME) play important roles in the occurrence and development of lung adenocarcinoma (LUAD). METHODS: In this study, we constructed a novel and reliable algorithm based on m6A-related immune lncRNAs (mrilncRNAs), consisting of molecular subtypes and a prognostic signature. RESULTS: According to the analyses of molecular subtypes, patients in cluster 1 were in a more advanced stage, showed poor prognosis, were sensitive to immunotherapy (anti-programmed cell death 1 Ligand 1 (PD-L1) and anti-lymphocyte activating 3 (LAG-3)), and had a highest tumor mutational burden (TMB), while anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy seemed to be a good choice for patients in cluster 3. Subsequently, the results of the risk assessment model indicated that the low-risk patients exhibited a survival advantage, had an earlier stage, and showed a higher response to common anti-cancer drugs, including chemotherapy (Docetaxel, Paclitaxel), molecular targeted therapy (Erlotinib), and immunotherapy (anti-CTLA-4 therapy), while Gefitinib could be a good choice for patients with high-risk scores. CONCLUSION: In conclusion, the constructed algorithm exhibits promising practical prospects, and allows the selection of suitable and sensitive anti-cancer drugs, which could provide theoretical support to predict the survival outcomes of patients with LUAD.

The diagnostic value of has_circ_0006423 in non-small cell lung cancer and its role as a tumor suppressor gene that sponges miR-492.

The diagnosis and treatment of non-small cell lung cancer (NSCLC) are not ideal. We identified NSCLC-related has_circ_0006423 in database. qRT-PCR was used to measure expression levels of hsa_circ_0006423 and miR-492 in the plasma and tissue samples, and 3 NSCLC cell lines, respectively. We analyzed the relationship between expression levels of hsa_circ_0006423 and clinicopathological factors and miR-492 expression in plasma and tissue samples. Assess the diagnostic value of hsa_circ_0006423 and miR-492 in NSCLC. Cell function vitro experiment to explore the effect of has_circ_0006423 on NSCLC. We found has_circ_0006423 is lower expressed in NSCLC and miR-492 is opposite, has_circ_0006423 and miR-492 has diagnostic value in NSCLC. In A549 and NCI-H1299 cells, hsa_circ_0006423 inhibited the proliferation, migration, and invasion of NSCLC cells by sponging miR-492 and accelerating NSCLC cell apoptosis. This effect may be due to the combination of has_circ_0006423 and miR-492 affecting the progression of NSCLC.

Hsa_circ_0000437 upregulates and promotes disease progression in rheumatic valvular heart disease.

BACKGROUND: Currently, the diagnosis and outcome of rheumatic valvular heart disease (RVHD) are less than ideal, and there are no accurate biomarkers. Circular RNA (circRNA) might participate in the occurrence and development of RVHD. MATERIALS AND METHODS: We use circRNA microarray to filter out the target has_circ_0000437. qRT-PCR was used to measure the expression levels of hsa_circ_0000437 in RVHD plasma samples. We assessed the diagnostic value of hsa_circ_0000437 in RVHD. Cell function in vitro experiment was to explore the effect of has_circ_0000437 on RVHD. RESULTS: Has_circ_0000437 is highly expressed in RVHD (p < 0.001). has_circ_0000437 has the diagnostic value in RVHD. In RVHD, hsa_circ_0000437 can promote cell proliferation and migration but inhibits its apoptosis. This may be due to the combination of has_circ_0000437 and target miRNA in the cytoplasm that affects the progress of RVHD. CONCLUSIONS: Has_circ_0000437 can promote the process of RVHD and may be a potential for the diagnosis and treatment of RVHD.

BMPR2 promoter methylation and its expression in valvular heart disease complicated with pulmonary artery hypertension.

Valvular heart disease (VHD) is a common heart disease that affects blood flow. It usually requires heart surgery. Valvular heart disease complicated with pulmonary artery hypertension (VHD-PAH) may be lethal due to heart failure that results from increased heart burden. It is important for these patients to seek early treatment in order to minimize the heart damage. However, there is no reliable diagnosis method in VHD. In this study, we found DNA methylation was increased at the promoter of BMPR2 gene in the VHD patients compared with the healthy controls. This finding was confirmed by an independent cohort study of VHD patients and healthy controls. In addition, BMPR2 mRNA levels were reduced in the plasma of the VHD patients. There is strong correlation between BMPR2 promoter DNA methylation and the severity of VHD. Indeed, we found that both BMPR2 promoter DNA methylation and BMPR2 mRNA levels in the plasma are good biomarkers of VHD by themselves, with the respective AUC value of 0.879 and 0.725, respectively. When they were used in combination, the diagnostic value was even better, with the AUC value of 0.93. Consistent with the results in the VHD patients, we observed decreased BMPR2 and increased fibrosis in the lung of a PAH model mouse. BMPR2 was also decreased in the hearts of the PAH mice, whereas BMP4 was increased. Furthermore, BMPR2 was reduced in the heart valve tissue samples of human VHD patients after valve replacement with moderate/severe PAH compared with those with mild PAH. There was also increased apoptosis in the hearts of the PAH mice. BMPR2 promoter DNA methylation and its expression appear to be good biomarkers for VHD. Our results also suggest that DNA methylation may cause PAH through deregulation of BMP signaling and increased apoptosis.

Effects of Spironolactone on Hypoxia-Inducible Factor-1α in the Patients Receiving Coronary Artery Bypass Grafting.

ABSTRACT: We explored the protective effect of spironolactone on cardiac function in the patients undergoing coronary artery bypass grafting (CABG) by determining serum hypoxia-inducible factor-1α (HIF-1α) before and after CABG. We used the propensity score matching method retrospectively to select 174 patients undergoing CABG in our hospital from March 2018 to December 2019. Of the 174 patients, 87 patients taking spironolactone for more than 3 months before CABG were used as a test group and other 87 patients who were not taking spironolactone as a control group. In all patients, serum HIF-1α and troponin I levels were determined before as well as 24 hours and 7 days after CABG, serum N-terminal probrain natriuretic peptide (NT-proBNP) level was determined before as well as 12, 24, and 36 hours after CABG, and electrocardiographic monitoring was performed within 36 hours after CABG. The results indicated that there were no significant differences in the HIF-1α level between the test group and the control group before and 7 days after CABG, but the HIF-1α level was significantly lower in the test group than that in the control group 24 hours after CABG (P < 0.01). The 2 groups were not significantly different in the troponin I level at any time point. There was no significant difference in the serum NT-proBNP level between the test group and the control group before CABG, but NT-proBNP (BNP) levels were all significantly lower in the test group than those in the control group at postoperative 12, 24, and 36 hour time points (all P <0.05). The incidence of postoperative atrial fibrillation was also significantly lower in the test group than that in the control group (P = 0.035). Spironolactone protects cardiac function probably by improving myocardial hypoxia and inhibiting myocardial remodeling.

Identification and Functional Prediction of Long Non-Coding RNAs in Dilated Cardiomyopathy by Bioinformatics Analysis.

Dilated cardiomyopathy (DCM) is a relatively common cause of heart failure and the leading cause of heart transplantation. Aberrant changes in long non-coding RNAs (lncRNAs) are involved in DCM disorder; however, the detailed mechanisms underlying DCM initiation and progression require further investigation, and new molecular targets are needed. Here, we obtained lncRNA-expression profiles associated with DCM and non-failing hearts through microarray probe-sequence re-annotation. Weighted gene co-expression network analysis revealed a module highly associated with DCM status. Then eight hub lncRNAs in this module (FGD5-AS1, AC009113.1, WDFY3-AS2, NIFK-AS1, ZNF571-AS1, MIR100HG, AC079089.1, and EIF3J-AS1) were identified. All hub lncRNAs except ZNF571-AS1 were predicted as localizing to the cytoplasm. As a possible mechanism of DCM pathogenesis, we predicted that these hub lncRNAs might exert functions by acting as competing endogenous RNAs (ceRNAs). Furthermore, we found that the above results can be essentially reproduced in an independent external dataset. We observed the localization of hub lncRNAs by RNA-FISH in human aortic smooth muscle cells and confirmed the upregulation of the hub lncRNAs in DCM patients through quantitative RT-PCR. In conclusion, these findings identified eight candidate lncRNAs associated with DCM disease and revealed their potential involvement in DCM partly through ceRNA crosstalk. Our results facilitate the discovery of therapeutic targets and enhance the understanding of DCM pathogenesis.

The effects of novel coronavirus (SARS-CoV-2) infection on cardiovascular diseases and cardiopulmonary injuries.

COVID-19 caused by a novel coronavirus named SARS-CoV-2, can elites severe acute respiratory syndrome, severe lung injury, cardiac injury, and even death and became a worldwide pandemic. SARS-CoV-2 infection may result in cardiac injury via several mechanisms, including the expression of angiotensin-converting enzyme 2 (ACE2) receptor and leading to a cytokine storm, can elicit an exaggerated host immune response. This response contributes to multi-organ dysfunction. As an emerging infectious disease, there are limited data on the effects of this infection on patients with underlying cardiovascular comorbidities. In this review, we summarize the early-stage clinical experiences with COVID-19, with particular focus on patients with cardiovascular diseases and cardiopulmonary injuries, and explores potential available evidence regarding the association between COVID-19, and cardiovascular complications.

Non-coding RNAs: The key detectors and regulators in cardiovascular disease.

Cardiovascular disease (CVD) is an important cause of disease-related death worldwide. One of its main pathological bases is imbalances in gene expression. Non-coding RNAs are a class of transcripts that do not encode proteins. They include microRNA (miRNA), long noncoding RNA (lncRNA) and circular RNA (circRNA). They have important biological functions such as regulating transcription and translation, as well as interacting with DNA, RNA, and proteins. They are also closely associated with pathological processes in CVD. This review will focus on the expression and function of miRNA, lncRNA, circRNA, as well as on their roles and molecular mechanisms in CVDs such as cardiac hypertrophy, heart failure, arrhythmia, myocardial infarction, atherosclerosis, rheumatic heart disease, myocardial fibrosis, pulmonary arterial hypertension. This review will outline concepts provide bases for early diagnosis and targeted treatment of CVDs.

miRNA-1183-targeted regulation of Bcl-2 contributes to the pathogenesis of rheumatic heart disease.

To determine whether up-regulation of miR-1183 targeting the gene for anti-apoptotic factor, B-cell lymphoma 2 (BCL-2) contributes to apoptosis in patients with rheumatic heart disease (RHD). Peripheral blood samples were isolated for miR-1183 characterization. The function of miRNA-1183 in RHD using miRNA mimic on PBMCs and THP-1 cell models. The binding of miR-1183 and Bcl-2 gene was confirmed by luciferase activity test. We also measured expression levels of BCL-2 in heart valve tissue from patients with RHD using ELISA and immunohistochemistry. In silico analysis and reporter gene assays indicated that miR-1183 directly targets the mRNA encoding BCL-2. It is found that miR-1183 binds directly to the 3'UTR of the BCL-2 mRNA and down-regulates the mRNA and protein levels of BCL-2. Overexpression of miR-1183 in RHD patients and cell lines down-regulated BCL-2 expression and induced apoptosis. With the progression of the disease, the expression of BCL-2 in the heart valve tissue of patients with RHD decreased. MiRNA-1183 is up-regulated in RHD and induces cardiac myocyte apoptosis through direct targeting and suppression of BCL-2, both of which might play important roles in RHD pathogenesis. During the compensatory period of RHD, up-regulated miR-1183 destroyed the balance of apoptosis proteins (Bax and BAK) in Bcl-2 family, enhance the apoptosis cascade reaction and reduce the anti apoptosis effect. The significantly higher expression levels of miR-1183 appear to play distinct roles in RHD pathogenesis by regulation BCL-2, possibly affecting myocardial apoptosis and remodeling in the context of RHD.

Efficient detection of differentially methylated regions in the genome of patients with thoracic aortic dissection and association with MMP2 hypermethylation.

DNA methylation is known to regulate the expression of numerous genes but its role in the pathogenesis of thoracic aortic dissection (TAD) has remained largely elusive. In the present study, the DNA methylome of patients with TAD was analyzed using a methylation microarray and bisulfite pyrosequencing was used to determine whether the hypermethylation of matrix metalloproteinase 2 (MMP2) specifically is associated with TAD. Chip-based whole-DNA methylome analysis was performed on 4 male patients with TAD and 4 male healthy controls using an Illumina HumanMethylation EPIC 850K BeadChip. The resulting data were analyzed by clustering and principal component analysis, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the differentially methylated genes to interrogate their biological functions. Compared to the healthy controls, 3,362 loci were differentially methylated in the patients with TAD with a statistical significance of P<0.05, while 1,223 loci had a significance of P<0.01. Among these loci, 2,019 were hypermethylated and 1,343 were hypomethylated. From GO analysis within the biological process category, the MMP2, MMP14 and WNT2B genes were identified. enrichment was observed for loci involved in cellular component organization, enzyme-linked receptor protein signaling pathways (potentially having a key role in the development of cardiopulmonary function disorders) and vascular reconstruction. Bisulfite pyrosequencing of plasma samples indicated significantly increased methylation (P<0.01) of the CpG site at position 2 in the promoter of MMP2 in the TAD group relative to the healthy controls, and the mean methylation level of four CpG sites on the MMP2 gene in the TAD group was slightly higher than that in the control group, but not significantly. Hypermethylation of the MMP2 promoter may be a promising novel diagnostic and prognostic biomarker for TAD. Future studies on the epigenetics of biomarkers linked to vascular reconstruction and immune function may provide further insight into the pathogenesis and progression of TAD.